The 133-kDa N-terminal domain enables myosin 15 to maintain mechanotransducing stereocilia and is essential for hearing.
The 133-kDa N-terminal domain enables myosin 15 to maintain mechanotransducing stereocilia and is essential for hearing.
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DOI：
10.7554/elife.08627
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发表时间：
2015-08-24
期刊：
影响因子：
7.7
通讯作者：
Bird JE
中科院分区：
文献类型：
--
作者：
Fang Q;Indzhykulian AA;Mustapha M;Riordan GP;Dolan DF;Friedman TB;Belyantseva IA;Frolenkov GI;Camper SA;Bird JE
内耳毛细胞静纤毛的精确组装成高度增加的行对于机械传导和听觉是至关重要的。然而，肌动蛋白为基础的静纤毛的长度是如何调节仍然知之甚少。分子马达肌球蛋白15的突变阻碍静纤毛的生长并导致耳聋。我们发现，毛细胞表达两种亚型的肌球蛋白15不同的133-kDa的N-末端结构域的列入，这些亚型可以选择性地交通到不同的静纤毛行。使用同种型特异性基因敲除小鼠，我们表明，毛细胞只表达小亚型显着发展正常静纤毛束。然而，一个关键的子集静纤毛与积极mechanotransducer通道随后收回。具有133 kDa N-末端结构域的较大同种型运输这些专门的静纤毛并防止其肌动蛋白核心的分解。我们的研究结果表明，肌球蛋白15异构体可以导航功能不同类的静纤毛，并独立需要组装，然后保持复杂的毛束结构。声音是由耳蜗检测到的，耳蜗是一种包裹在人类和其他哺乳动物内耳内的卷曲结构。在这个器官内，复杂的感觉毛细胞阵列受到声音的刺激，产生传递到大脑的神经信号。毛细胞的名字来源于“毛发”，实际上是一种叫做静纤毛的结构，它的作用就像天线一样，可以探测声波。通过基因突变或噪音对这些精密的机械传感器造成的损害是人类听力损失的重要原因。一种叫做肌球蛋白15的蛋白质是静纤毛发育和生长到正常高度所需的分子马达。这种蛋白质的突变会导致人类遗传性耳聋。毛细胞产生两种形式的肌球蛋白15，它们是相同的，除了一种形式有一个额外的区域称为N-末端延伸。利用基因工程，Fang等人创造了突变小鼠，这些小鼠只产生缺乏N-末端延伸的较小版本的肌球蛋白15。这些突变小鼠帮助揭示，当毛细胞年轻时，它们主要产生较小版本的肌球蛋白15，这足以使静纤毛正常生长。然而，一旦毛细胞成熟，它们就会转而产生含有N-末端延伸的较大版本的肌球蛋白15。在缺乏较大版本肌球蛋白15的突变小鼠中，静纤毛最终恶化，使毛细胞无法检测声音。以前已知肌球蛋白15有助于静纤毛生长，但Fang等人现在表明，这种蛋白质也是维持静纤毛一生所必需的。下一个挑战是了解N-末端延伸如何使肌球蛋白15保持成人静纤毛的结构，并研究是否可以刺激这种活动以防止听力损失。DOI：www.example.com网站
The precise assembly of inner ear hair cell stereocilia into rows of increasing height is critical for mechanotransduction and the sense of hearing. Yet, how the lengths of actin-based stereocilia are regulated remains poorly understood. Mutations of the molecular motor myosin 15 stunt stereocilia growth and cause deafness. We found that hair cells express two isoforms of myosin 15 that differ by inclusion of an 133-kDa N-terminal domain, and that these isoforms can selectively traffic to different stereocilia rows. Using an isoform-specific knockout mouse, we show that hair cells expressing only the small isoform remarkably develop normal stereocilia bundles. However, a critical subset of stereocilia with active mechanotransducer channels subsequently retracts. The larger isoform with the 133-kDa N-terminal domain traffics to these specialized stereocilia and prevents disassembly of their actin core. Our results show that myosin 15 isoforms can navigate between functionally distinct classes of stereocilia, and are independently required to assemble and then maintain the intricate hair bundle architecture. DOI: http://dx.doi.org/10.7554/eLife.08627.001 Sound is detected by the cochlea, a coiled structure encapsulated within the inner ear of humans and other mammals. Inside this organ, intricate arrays of sensory hair cells are stimulated by sound to generate neural signals that are transmitted to the brain. The ‘hairs’ that give hair cells their name are actually structures called stereocilia that act like antennas to detect sound waves. Damage to these delicate mechanical sensors, through genetic mutations or loud noise, are a significant cause of hearing loss in humans. A protein called myosin 15 is a molecular motor needed for stereocilia to develop and grow to their normal height. Mutations of this protein cause hereditary deafness in humans. Hair cells produce two versions of myosin 15, which are identical except for one version having an extra region called the N-terminal extension. Using genetic engineering, Fang et al. created mutant mice that only produce the smaller version of myosin 15 that lack the N-terminal extension. These mutant mice helped reveal that when hair cells are young, they mostly produce the smaller version of myosin 15, and this is sufficient for stereocilia to grow normally. Once hair cells mature however, they switch to producing the larger version of myosin 15 that contains the N-terminal extension. In the mutant mice that lacked the larger version of myosin 15, stereocilia ultimately deteriorate, leaving the hair cells unable to detect sound. Myosin 15 was previously known to help stereocilia grow, but Fang et al. now show that this protein is also required to maintain stereocilia throughout life. The next challenge is to understand how the N-terminal extension enables myosin 15 to preserve the structure of adult stereocilia, and to investigate whether this activity might be stimulated to prevent hearing loss. DOI: http://dx.doi.org/10.7554/eLife.08627.002